TrkA kinase inhibitors, compositions and methods thereof

Abstract

The present invention is directed to six membered heteroaryl benzamide compounds of formula (I), which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.

What is claimed is: 
     
       1. A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein:
 B represents a six membered heteroaryl having at least one heteroatom that is nitrogen, said heteroaryl optionally substituted with 1 to 3 groups of R a ; 
 R represents hydrogen, OH, or —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R f ; 
 R 1  is selected from the group consisting of hydrogen, CN, OH, —C 1-6 alkyl and halogen; 
 R 2  is hydrogen or (CHR) n C 5-10  heterocycle, said heterocycle optionally substituted with 1 to 3 groups of R a , wherein when R 2  is hydrogen then R 4  is (CHR) n C 5-10  heterocycle; 
 R 4  is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, (CHR) n C 6-10  aryl and (CHR) n C 5-10  heterocycle, said alkyl, aryl, and heterocycle optionally substituted with 1 to 3 groups of R a , 
 R 3  represents C 1-4  haloalkyl, 
 R 5  is hydrogen or halogen; 
 R a  is selected from the group consisting of hydrogen, —CN, NO 2 , —(CH 2 ) n C(O)OR f , —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, —C 1-6 alkynyl, —(CH 2 ) n C 3-6 cycloalkyl, —(CHR) n C 6-10  aryl, —(CHR) n C 4-10  heterocycle, —(CH 2 ) n C(O)(CHR) n C 4-10  heterocycle, —O—(CH 2 ) n C 6-10  aryl, —O—(CH 2 ) n C 4-10  heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, SO 2 R d , (CH 2 ) n NHSO 2 R d , —(CH 2 ) n SO 2 N(R d ) 2 , S(O)(NH)R g , —C(O)CF 3 , COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NRC(O)NHR d , —(CH 2 ) n NHC(O)OR d , CHR) n C(O)N(R d ) 2  —OC 1-6 alkyl, —O—, and —OH, said alkyl, cycloalkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein when two R d  groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocyle that is optionally substituted with 1 to 3 groups of R f ; 
 R b  is selected from the group consisting of halogen, —C 1-6 alkyl, —C 1-6 alkylOR, —C 1-4 haloalkyl, —(CH 2 ) n N(R d ) 2 , —OR c , —O—, —CN, S(O)(NH)R g , —SO 2 R, —SO 2 N(R d ) 2 , —(CH 2 ) n C(O)N(R d ) 2 , —(CH 2 ) n NHC(O)R d , COR, C(O)OR, C 3-6 cycloalkyl, —O—(CH 2 ) n C 4-10  heterocycle, and —C 1-6 alkylN(R d ) 2 , said alkyl and heterocycle optionally substituted with 1 to 3 groups of R f ; 
 R c  is selected from the group consisting of hydrogen, —C 1-6 alkylORg, —C 1-4 haloalkyl and —C 1-6 alkyl; 
 R d  is independently selected from the group consisting of hydrogen, halogen, —C 1-4 haloalkyl —C 1-6 alkyl, COR, —(CH 2 ) n SO 2 R, —(CH 2 ) n NR f C 4-10  heterocycle, —(CH 2 ) n C 3-6 cycloalkyl, —(CH 2 ) n C 4-10 heterocycle said alkyl, cycloalkyl and heterocycle optionally substituted with 1 to 3 groups of R f ; wherein when two R d  groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocyle that is optionally substituted with 1 to 3 groups of R f ; 
 R f  is selected from the group consisting of hydrogen, C 1-6 alkyl, OR c , CN, —N(R c ) 2 , C(O)N(R g ) 2 , C(O)C 1-6 alkyl, —SO 2 R g , —O—, —C 1-6 alkylSO 2 R g , —C 1-6 alkylOR g , —C 1-6 alkylN(R g ) 2 , 
 R g  is selected from the group consisting of hydrogen, —C 1-6 alkyl; and 
 n represents 0-6. 
 
     
     
       2. The compound according to  claim 1  wherein B is an unsubstituted or substituted six membered heterocycle selected from the group consisting of pyridyl, pyrimidinyl, pyradizinyl, and pyrazinyl. 
     
     
       3. The compound according to  claim 2  wherein B is unsubstituted or substituted pyridyl. 
     
     
       4. The compound according to  claim 2  wherein B is unsubstituted or substituted pyrimidinyl. 
     
     
       5. The compound according to  claim 1  wherein one of R 2  and R 4  is hydrogen and the other is optionally substituted (CHR) n C 5-10  heterocycle and R 1  and R 5  are independently selected from hydrogen and halogen. 
     
     
       6. The compound according to  claim 5  wherein the heterocycle of R 2  and R 4  is selected from the group consisting of optionally substituted pyrazolyl, pyridyl, thiazolyl, triazolyl, oxazolyl, oxadiazolyl, and pyrimidinyl. 
     
     
       7. The compound according to  claim 1  wherein R 3  is CF 3 . 
     
     
       8. The compound according to  claim 1  wherein B is a pyrimidinyl substituted with 1 to 3 groups of R a  selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10  aryl, —(CHR) n C 4-10  heterocycle, —C(O)(CHR) n C 4-10  heterocycle, —O—(CH 2 ) n C 6- 10  aryl, —O—(CH 2 ) n C 4-10  heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10  heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2  —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2. 
     
     
       9. The compound according to  claim 1  wherein B is a pyridyl substituted with 1 to 3 groups of R a  selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10  aryl, —(CHR) n C 4-10  heterocycle, —C(O)(CHR) n C 4-10  heterocycle, —O—(CH 2 ) n C 6-10  aryl, —O—(CH 2 ) n C 4-10  heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10  heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2  —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2. 
     
     
       10. The compound according to  claim 1  represented by structural formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5  are as originally described and R a1 , R a2 , R a3 , and R a4  all equal R a  and R a  is as originally described. 
     
     
       11. The compound according to  claim 10  wherein R a1 , R a2 , R a3 , and R a4  are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10  aryl, —(CHR) n C 4-10  heterocycle, —C(O)(CHR) n C 4-10  heterocycle, —O—(CH 2 ) n C 6-10  aryl, —O—(CH 2 ) n C 4- 10  heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10  heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein at least two of R a1 , R a2 , R a3 , and R a4  on the pryidyl are hydrogen, and one of R a1 , R a2 , R a3 , and R a4  is phenyl, R 1  and R 5  are independently selected from hydrogen and halogen, R 3  is CF 3 , or halogen, and one of R 2  and R 4  is hydrogen and the other is (CHR) n C 5-10  heterocycle. 
     
     
       12. The compound according to  claim 10  wherein R a4  is phenyl, R 1  is hydrogen, R 3  is CF 3 , R 5  is fluorine, R 2  is optionally substituted pyrazolyl, and R 4  is hydrogen. 
     
     
       13. The compound according to  claim 1  represented by structural formula II: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5  are as originally described, and R w , R v  and R y =R a . 
     
     
       14. The compound according to  claim 13  wherein R w , R v , and R y  are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10  aryl, —(CHR) n C 4-10  heterocycle, —C(O)(CHR) n C 4-10  heterocycle, —O—(CH 2 ) n C 6-10  aryl, —O—(CH 2 ) n C 4-10  heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10  heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein at least two of R w , R v , and R y  on the pryimidinyl are hydrogen, and one of R w , R v , and R y  is phenyl, R 1  and R 5  are independently selected from hydrogen and halogen, R 3  is CF 3 , or halogen, and one of R 2  and R 4  is hydrogen and the other is (CHR) n C 5-10  heterocycle. 
     
     
       15. The compound according to  claim 13  wherein R w  is phenyl, R 1  is hydrogen, R 3  is CF 3 , R 5  is fluorine, R 2  is optionally substituted pyrazolyl, and R 4  is hydrogen. 
     
     
       16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.